Insulin & Hypoglycaemics Flashcards
What Does Insulin Do?
Increase Glucose Uptake, Storage & Utilization Increase Protein Synthesis Increase Triglyceride Synthesis Increase Gene Expression & Growth Decrease Proteolysis Decrease Lipolysis and Lipid Oxidation
What is the Mode of Action of Insulin?
- Receptor Activation
- Signal Transduction
- Signalling Cascades Mediated by IRS2
- Functional Effects
What are the objectives of diabetes treatment?
Achieve normoglycaemia
Return blood pressure & cholesterol levels to normal
Adopt a healthy lifestyle to protect against long-term complications.
Broad Treatment plans of T1DM
lifelong insulin, healthydiet, regular exercise
Broad Treatment plans of T2DM
Lifestyle changes (diet, weight, activity). Hypoglycaemic therapy and/or insulin.
Name short duration and rapid onset insulin therapy?
insulin aspart, insulin glulisine, insulin lispro
Given sc or iv
onset = 30-60mins
peak action - 2-4hours
Injected just before, with or just after food and only lasts long enough for the meal at which it is are taken.
Name Intermediate / Longer Duration onset insulin therapy?
Insulin detemir insulin glargine insulin zinc suspension isophane insulin protamine zinc insulin
Onset = 1-2hours Peak = 4-12houes Duration = 16-35hours
Biphasic Insulin Preparations
Mixture of intermediate & fast acting
Rapid onset
Long-lasting actions
Glucagon Therapy
Taken to promote =
- Glycogenolysis (glycogen to glucose)
- Gluconeogenesis
- Lipolysis (fat to FAs)
First-aid treatment for severe hypoglycaemia when oral glucose is not possible or desired
Route: injection; intramuscular, intravenous or subcutaneous
Must be reconstituted prior to use
Acutely raises plasma glucose levels
Common side-effects include headache and nausea
T2DM Therapies Secretagogues I - all end in IDE
Two types, noth thave the same action = boost insulin release; enhance the normal physiology of glucose-stimulated insulin secretion. Antagonists of Katp channel
Sulphonylureas
Meglitinides
Sulphonylureas
Small molecule antagonists of the KATP Channel
Taken oral, twice daily, pre meal usually combined with other therapies
Short Lasting Formulations: gliclazide (Diamicron); tolbutamide (Orinase)
Long-Lasting Formulations: chlorpropamide (Diabinese); glibenclamide; glipizide (Glucotrol); glimepiride (Amaryl)
side effects = hypoglycaemia
Meglitinides
Small molecule antagonists of the KATP Channel
Oral agents: Once or twice daily with or shortly before a meal
Short Acting = Repaglinide (Prandin®) and Nateglinide (Starlix®)
May have a decreased the risk of hypoglycaemia compared to SUs, particularly the elderly
Incretin Mimetics are Secretagogues That Have a Different Mode of Action! Why?
GLP-1 cannot be used as it has a very short half-life and is rapidly broken down by the endogenous enzyme dipeptydylpeptidase-4 (DPP-4)
How do Incretin Mimetic work? Background?
Boost insulin release by enhancing the normal physiology of incretin-mediated insulin secretion.
Peptide-Agonists of the GLP-1 Receptor and not broken down by dipeptydylpeptidase-4 (DPP-4)
Injectable agents, s.c.
Combined with other therapies
Much reduced risk of hypoglycaemia compared to sulphonylureas
Byetta
Secretagogues II
Exenatide and Liraglutide
Injection
Side effects = gastro-intestinal disturbances including nausea, vomiting, diarrhoea, dyspepsia, abdominal pain and distension, gastro-oesophageal reflux disease, decreased appetite; headache, dizziness, agitation, asthenia; increased sweating, injection-site reactions; antibody formation
Gliptins
Incretin Mimetic
Boost insulin release by enhancing the normal physiology of incretin-mediated insulin secretion.
Inhibitors of dipeptydylpeptidase-4 (DPP-4); raises the half-life of serum GLP-1
Tablet – Oral
Can be combined with other medications; novel formulations e.g. Eucreas®, Janume® - gliptins+metformin
Side-effects vomiting, dyspepsia, gastritis; peripheral oedema; headache, dizziness, fatigue; upper respiratory tract infection, urinary tract infection, gastroenteritis, sinusitis, nasopharyngitis; hypoglycaemia, myalgia; less commonly dyslipidaemia, hypertriglyceridaemia, erectile dysfunction, arthralgia; also reported rash
Diazoxide
To treat congenital hyperinsulinism in infancy, insulinomas, severes cases of transient hypoglycaemia
Small molecule agonist of the Katp channel
Side effects =
anorexia, nausea, vomiting, hyperuricaemia,
hypotension, oedema, tachycardia, arrhythmias,
extrapyramidal effects; hypertrichosis on prolonged treatment
Insulin Sensitizers
Insulin Sensitizers improve the sensitivity of target organs to insulin
There are two types =
- Biguanides = activating enzymes
- Thiazolidinediones = modifying the transcription of genes
The Mode of Action of Biguanides?
- Receptor Activation
- Signal Transduction
- Signalling Cascades Mediated by IRS2
- Agonist of AMP-activated protein kinase (AMPK)
Function effects =
Increase Glucose Uptake, Storage & Utilization, Protein Synthesis, Triglyceride Synthesis, Gene Expression & Growth
Decrease Proteolysis, Lipolysis and Lipid Oxidation
Basically prevents hepatic production of glucose, overcomes insulin resistance by improving insulin sensitivity
Metformin
Combinational Therapies
- pioglitazone (Actoplus Met)
- glipizide (Metaglip)
- glibenclamide (Glucovance),
- sitagliptin (Janumet),
- repaglinide (PrandiMet)
Thiazolidinediones / glitazones
Activate PPARγ, a regulatory protein involved in the transcription of insulin-sensitive genes which regulate glucose and fat metabolism
Target adipocytes
Oral - 1/2 daily
Rosiglitizone - can also be combined with metformin or
glimepiride
α-Glucosidase Inhibitors
Aim = Modifying Glucose Breakdown
Example = Acarbose
Action =
1. α-glucosidase converts oligosaccharides to glucose
2. Acarbose stops emzyme
3. slows absorb of fat foods
4. In patients, this provides a closer alignment of [impaired] insulin output with glucose uptake
Side effects = Flatulence, diarrhoea, abdominal pain, nausea, vomiting, indigestion, liver function problems, oedema, blood disorders, allergic skin reaction, intestinal problems.
SGLT2 Inhibitors - end in ZIN
Aim = Enhancing Glucose Release Examples = Dapagliflozin*, canagliflozin, empagliflozin
SGLT2 inhibitors cause excess glucose to be eliminated in the urine; reducing hyperglycaemia
Potential Advantages: weight loss, insulin independent, low risk of hypoglycaemia, osmotic diuresis reduces hypertension
